PROJECT SUMMARY/ABSTRACT Richter's transformation (RT) is an aggressive B-cell lymphoma that occurs in the setting of chronic lymphocytic leukemia (CLL). RT is therapy-resistant and associated with short survival and is the most common progression seen in patients receiving targeted therapies including the BTK inhibitor ibrutinib. The molecular mechanisms driving RT are unknown, but if identified, could yield discovery of potential therapeutic targets and predictive indicators for this incurable disease. BRD4 is a bromodomain-containing protein that regulates transcription of genes critical for cell growth and proliferation. Our preliminary results show BRD4 levels to increase during CLL disease progression and its inhibition to down-modulate key genes relevant to CLL and RT development. Moreover, our pilot studies revealed a unique BRD4-mediated immunomodulatory signature wherein co-inhibitory immune checkpoint molecules were reduced following BRD4 inhibition in primary tumor cells. To date the biology of BRD4, implication of its inhibition and its potential to correct immune defects has yet to be investigated in leukemia/lymphoma. We hypothesize that dysregulation of BRD4 functions as a driver of RT representing a novel therapeutic target for epigenetic intervention for this fatal disease. Two Specific Aims will address this: In Aim we will determine the role of BRD4 in CLL-to-RT biology and identify a novel gene signature underlying RT. In Aim 2 we will evaluate the anti-tumor and immunomodulatory properties of BRD4 inhibition as a therapeutic epigenetic intervention approach for aggressive CLL and RT. This study, if successful, will promote the development of diagnostic and prognostic tests/markers predictive of CLL transformation to lymphoma and introduce novel therapeutic approaches for this incurable disease.